The primate menstrual cycle is characterized by a proliferation and regression of the uterine lining under the control of steroid hormones, primarily estrogen and progesterone. It is believed that the staggered cyclic levels of hormones contribute to the growth and shedding of the upper tissue compartment of the uterus.
The endometrium on the uterus is characterized by distinct layers, such as the stratum functionalis and stratum basalis. It is the functionalis which represents the transient upper tissue compartment that is shed during menstruation.
It is believed that the basalis serves as a source of new cells for the regeneration of the functionalis in succeeding cycles. Wilborn & Flowers, Seminars in Reproductive Endocrinology 2:4, 307, 1984; Padykula et al., Biology of Reproduction 40, 681, 1989. If the basalis does serve as a germinal layer, then the effects of damage to the basalis during a given cycle could be manifest in succeeding cycles.
Because endometrial proliferation serves to prepare the uterus for an impending pregnancy, manipulation of hormones and of the uterine environment can serve as suitable targets for contraception. For example, estrogens are known to decrease follicle stimulating hormone secretion by feedback inhibition.
Under certain circumstances, estrogens can also inhibit luteinizing hormone secretion, once again by negative feedback, although under normal circumstances it is believed that the spike of circulating estrogen found just prior to ovulation induces the surge of gonadotrophin hormones that occurs just prior to and resulting in ovulation. High doses of estrogen also can prevent conception probably due to interference with implantation.
Progesterone is responsible for the progestational changes of the endometrium and the cyclic changes of cells and tissues in the cervix and the vagina. For example, progesterone makes the cervical mucus thick, tenacious and cellular. It is believed that thickened mucus impedes spermatozoal transport.
Progesterone has somewhat of an anti-estrogenic effect on the myometrial cells, for example, decreasing the excitability of the smooth muscle cells, and the like. It is known that large doses of progesterone inhibit luteinizing hormone secretion and progesterone injections can prevent ovulation in humans.
The most prevalent form of oral contraception is a pill that combines both an estrogen and a progestagen, the so-called combined oral contraceptive preparations. Apparently, the estrogen and progestagen act in concert to block gonadotrophin release.
Alternatively, there are oral contraceptive preparations that comprise a progestagen only. Such preparations are indicated particularly for individuals who have experienced side effects or an intolerance to the combined preparations or in lactating women because of the lack of an estrogenic effect on lactation.
However, the progestagen-only preparations have a more varied spectrum of side effects than do the combined preparations. A disadvantage of the progestagen-only preparations is the relatively high incidence of bleeding problems, such as, prevalent or heavier menstrual spotting, amenorrhea and more breakthrough bleeding. Thus, the combined preparations are the preferred oral contraceptives in use today. Sheth et al., Contraception 25,243, 1982.
Some of the very common side effects of the progestagen-only oral contraceptives is the increased incidence of menstrual spotting, break. through bleeding, variations in menstrual cycle length and occasionally amenorrhea.
Nevertheless, it would be preferable to have an contraceptive preparation that minimizes the amounts of estrogens and progestagens used. For example, estrogens are known to cause dizziness, nausea, headache and breast tenderness. Thus, a progestagen-only contraceptive would forego such possible problems and be an improvement over the combined preparations if the above-referred to problems of progestagen-only contraceptives also can be remedied. George Washington University Medical Center, Population Reports, Series A, No. 3, September 1975.
Anti-progestins include inhibitors of progesterone synthesis, ligands, such as antibodies, to progesterone and progesterone receptor antagonists. For example, mifepristone (RU486) is a progesterone receptor antagonist. RU486 binds to the progesterone receptor and produces antagonistic effects. Following oral administration, RU486 in the human has a half life of about 20-24 hours. When administered in the luteal phase of the menstrual cycle, RU486 induces luteolysis and vaginal bleeding.
RU486 may act directly on the endometrium to induce vaginal bleeding. RU486-mediated luteolysis appears to be secondary to changes in gonadotrophin secretion and thus the effects are similar to those following exogenous progesterone administration. Baulieu, Science 245, 1351, 1989.
Swahn et al. (Human Reproduction 5(4), 402, 1990) relates to administering RU486 early during the luteal phase prior to implantation. Those authors found that a single dose of RU486 administered on the second day after the LH peak causes a retardation of endometrial development, without upsetting the menstrual cycle. Those authors speculated that it may be possible that the effect on the endometrium may be sufficient to prevent implantation.